Abstract：
Adult T-cell leukemia (ATL), caused by HTLV-1, is the most lethal hematological malignancy. NEDD8-activating enzyme (NAE) is a component of the NEDD8 conjunction pathway that regulates cullin-RING ubiquitin ligase (CRL) activity. HTLV-1-infected T cells expressed higher levels of NAE catalytic subunit UBA3 than normal peripheral blood mononuclear cells. NAE1 knockdown inhibited proliferation of HTLV-1-infected T cells. The NAE1 inhibitor MLN4924 suppressed neddylation of cullin and inhibited the CRL-mediated turnover of tumor suppressor proteins. MLN4924 inhibited proliferation of HTLV-1-infected T cells by inducing DNA damage, leading to S phase arrest and caspase-dependent apoptosis. S phase arrest was associated with CDK2 and cyclin A downregulation. MLN4924-induced apoptosis was mediated by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, MLN4924 inhibited NF-κB, AP-1, and Akt signaling pathways and activated JNK. Therefore, neddylation inhibition is an attractive strategy for ATL therapy. Our findings support the use of MLN4924 in ATL clinical trials.
摘要：
成人T细胞白血病(ATL),由HTLV-1引起的，是最致命的血液恶性肿瘤。NEDD8激活酶（NAE）是NEDD8连接途径的组成部分，可调节cullin-RING泛素连接酶（CRL）活性。与正常外周血单核细胞相比，HTLV-1感染的T细胞表达更高水平的NAE催化亚基UBA3。NAE1敲低抑制HTLV-1感染的T细胞的增殖。NAE1抑制剂MLN4924抑制了cullin的neddylation，并抑制了CRL介导的肿瘤抑制蛋白的周转。MLN4924通过诱导DNA损伤抑制HTLV-1感染的T细胞增殖,导致S期阻滞和胱天蛋白酶依赖性凋亡。S期阻滞与CDK2和细胞周期蛋白A下调有关。MLN4924诱导的细胞凋亡由促凋亡蛋白的上调和抗凋亡蛋白的下调介导。此外，MLN4924抑制NF-κB,AP-1和Akt信号通路和激活的JNK。因此,Neddylation抑制是ATL治疗的有吸引力的策略。我们的发现支持在ATL临床试验中使用MLN4924。
